The primary aim of the proposed study is to meet the urgent need for theory-driven, empirically- informed, effective, and sustainable HIV prevention and care approaches for the unprecedented numbers of perinatally HIV-infected (PHIV+) youth in South Africa (SA). This study aims to 1) increase our understanding of behavioral and health risk in this emerging population, and 2) to examine the impact of a family/household-level intervention, the VUKA Family Program (VUKA), to promote youth overall health and mental health, and reduce behavioral risk. Informed by Social Action Theory, (SAT); and the PRISM (Practical, Robust Implementation and Sustainability Model) theoretical framework, VUKA is a cartoon-based intervention developed with intensive input from SA investigators, graphic artists, medical staff, adult caregivers and HIV+ adolescents. This application is built upon a long-standing collaboration among US and SA researchers and clinicians and the SA Department of Health (SADOH). We propose a full-scale randomized controlled trial (RCT) to examine the effectiveness, implementation, and integration processes associated with VUKA with a sample of 360 PHIV+ early adolescents (9 to 14 years of age) registered at 4 publicly financed pediatric HIV clinics in KwaZulu Natal, a SA province with one of the highest HIV seroprevalence rates. Youth and their family members will be randomly assigned to one of two study conditions: 1) VUKA or; 2) standard of care. A 3-wave experimental research design with assessments at baseline, 3 month (posttest) and 12 month follow-up from baseline will be employed to address the following Specific Aims. Aim #1 (Primary): To identify the behavioral (e.g., ART adherence, engagement in sexual and drug use behaviors), health (e.g., level of viremia, general health), and psychosocial (e.g mental health, connection to protective adult resources, social decision-making skills) risks of the emerging population of PHIV+ youth in South Africa, guided by our SAT model (Figure 1) and based on baseline data collected as part of the proposed RCT. Aim #2 (Primary): To examine the impact of VUKA on youth behavioral, health and psychosocial outcomes relative to those who receive standard care within South African public medical clinics. Aim #3 (Secondary): To investigate how outcomes are mediated by theoretical constructs in our SAT model (self-regulation, social/family regulation, and contextual factors); Aim #4 (Secondary): To elucidate multi-level factors guided by PRISM that influence implementation, and integration of VUKA (e.g. staff delivery skill, perceptions of burden, clinic organizational challenges, time and space constraints) in publicly funded, pediatric HIV care sites in KwaZulu-Natal, SA). PUBLIC HEALTH RELEVANCE: The primary aim of the proposed study is to meet the urgent need for theory-driven, empirically- informed, effective, and sustainable HIV prevention and care approaches for the unprecedented numbers of perinatally HIV-infected (PHIV+) youth in South Africa. With one of the highest HIV prevalence rates in the world, communities within KwaZulu-Natal and the South Africa Department of Health are severely challenged to meet the complex needs of a growing number of surviving perinatally HIV-infected youth who must now cope with HIV as a chronic, highly stigmatized, and transmittable illness. VUKA is an example of a much needed comprehensive intervention to address health, mental health and behavioral outcomes, with the potential to significantly advance HIV science and practice for PHIV+ youth in Africa.